Toxicity of neoadjuvant chemotherapy for Emphas

Authors: Jan C Drooger Bernadette A M HeemskerkGerritsen Nyrée Smallenbroek Cynthia Epskamp Caroline M Seynaeve Agnes Jager

Publish Date: 2016/04/09

Volume: 156, Issue: 3, Pages: 557-566

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Abstract

Treatment with neoadjuvant chemotherapy for breast cancer as currently given causes cell damage by induction of doublestrand DNA breaks Because BRCA1 and BRCA2 proteins play a role in the repair of DNA damage the efficacy of neoadjuvant chemotherapy may be increased in BRCA1/2associated breast cancer patients As a downside acute chemotherapyrelated toxicity may also be increased We selected all female patients who were treated at the Erasmus MC Cancer Institute with neoadjuvant chemotherapy for primary or locoregional recurrence of breast cancer PBC/LR between January 1 2004 and December 31 2014 The primary outcome was the relative total dose intensity RTDI calculated for anthracyclines and taxanes separately Secondary outcomes were the occurrence of febrile neutropenia delay in chemotherapy administration and switch to another chemotherapy regimen due to toxicity In total 701 patients treated for PBC/LR were eligible for data analyses among which 85 BRCA1/2 mutation carriers n = 67 BRCA1 and n = 18 BRCA2 The mean RTDI for anthracyclines was not significantly different between both groups 987  in the BRCA1/2 966  in the sporadic group p = 027 Also the mean RTDI for taxanes was not significantly different between the groups 936  in the BRCA1/2associated 900  in the sporadic group p = 012 Linear regression analysis revealed no significant effect of BRCA1/2 mutation carriership on the RTDIs No significant differences were found in the percentages of patients presenting with febrile neutropenia having a delay in chemotherapy administration or switching to an altered chemotherapy regimen Additionally the odds ratios showed no significant effect of BRCA1/2 mutation carriership on the secondary outcome variables Neoadjuvant chemotherapyrelated toxicity was not different between BRCA1/2associated and sporadic breast cancer patients suggesting that the DNA damage repair mechanism of noncancer cells with only one normal copy of either the BRCA1 or BRCA2 gene is sufficiently functional to handle acute chemotherapyassociated toxicityCarriers of a germline BRCA1/2 mutation by definition have one allele with a mutation in the BRCA1/2 gene while the gene on the other allele is intact In normal cells it seems that enough BRCA1 or BRCA2 protein is present for adequate functioning of cells in the various tissues of these women However BRCA1/2associated breast cancers often have lost the wildtype allele through somatic alterations during tumor development As a consequence there is no functional BRCA1 or BRCA2 protein in these tumor cells Since BRCA1 and BRCA2 proteins are essential in the repair of doublestrand DNA breaks DSBs by homologous recombination 3 4 treatments which cause DSBs might be more effective in BRCA1/2associated than in sporadic breast cancer patients which tumor cells mostly have an intact homologous recombination repair system The platinum derivates carboplatin and cisplatin both strong inducers of DSBs indeed showed higher efficacy in BRCA1/2associated compared to sporadic breast cancer patients 5 6 7 Although less pronounced anthracyclines are also known to induce indirect DSBs by inhibiting topoisomerases causing DNA interstrand crosslinks and the generation of free radicals 8 Accordingly several clinical studies have shown increased sensitivity for anthracyclinecontaining chemotherapy in BRCA1/2 mutation carriers 9 10 11An important question is whether acute toxicity due to neoadjuvant chemotherapy is different in BRCA1/2 mutation carriers treated for breast cancer when compared with sporadic breast cancer patients Since neoadjuvant chemotherapy induces massive DNA damage also in normal cells one might argue that the amount of functional BRCA1 or BRCA2 protein in mutation carriers is too low to repair all the DNA damage created compared to sporadic breast cancer patients resulting in more toxicity Thus far two studies investigated the acute toxicity of neoadjuvant chemotherapy in BRCA1/2associated compared to sporadic breast cancer patients with inconsistent results 12 13 In the retrospective study of Shanley et al comparing 62 BRCA1/2 mutation carriers with breast cancer to 62 matched sporadic breast cancer cases a large proportion of patients 80/124 65  was treated with older chemotherapy regimens without anthracyclines while no patient was treated with taxanes In BRCA2 mutation carriers less hematologic toxicity and dose alterations were observed compared to both BRCA1associated and sporadic breast cancer patients while no differences were seen for BRCA1associated versus sporadic patients 12 In the study by Huszno et al comparing 41 BRCA1/2associated with 229 breast cancer patients without a BRCA1/2 mutation all patients were treated with an anthracyclinebased regimen and also patients treated with taxanes were included 13 It was found that the proportion of patients with neutropenia at the planned start date of the second chemotherapy cycle was significantly higher in breast cancer patients with a BRCA1/2 mutation compared to patients without a BRCA1/2 mutation Twelve patients 45  all in the group of patients without a BRCA1/2 mutation required early termination of treatment due to chemotherapy toxicity mostly because of grade 34 neutropenia Nausea and vomiting were seen more often in patients without a BRCA1/2 mutation There were no differences in the other investigated variables anemia diarrhea and mucositisNowadays standard neoadjuvant chemotherapy regimens for breast cancer contain both anthracycline either epirubicin or doxorubicin and taxanes either paclitaxel or docetaxel In view of the sparse available data on toxicity of taxanes and currently used chemotherapy regimens in BRCA1/2 mutation carriers we performed a larger singlecenter retrospective cohort study to examine potential differences in neoadjuvant chemotherapyassociated toxicity between BRCA1/2associated and sporadic breast cancer patientsFor eligible patients data on tumor characteristics type of histology differentiation grade estrogen receptor status progesterone receptor status HER2 status and stage and treatment details surgery radiotherapy and/or chemotherapy were retrieved We also collected specific data on chemotherapy treatment treatment regimen dosing delays alterations and complications Data on mutation status were collected from the institutional database of the family cancer clinic Patients not tested for a BRCA1/2 mutation were considered as sporadic breast cancer patientsDuring the time period of the study the chemotherapy regimens were not different for BRCA1/2 mutation carriers and sporadic patients Patients were treated with systemic therapy based on the national guidelines For patients with HER2negative breast cancer the standard regimens at start of the study contained anthracyclines but no taxanes From July 2008 till the end of the study standard regimen for nodepositive patients included taxanes 3weekly docetaxel while for nodenegative patients taxanes 3weekly docetaxel were included in the standard regimen from October 2011 onwards Patients with HER2positive breast cancer were treated with anthracyclines and no taxanes till August 2006 Trastuzumab was added to this regimen from September 2005 onwards From August 2006 till the end of the study the standard regimen contained anthracyclines and taxanes weekly paclitaxel in combination with trastuzumab

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